Tumor necrosis factor alpha (TNF-alpha) is a pleiotropic inflammatory cytokine having a molecular weight of 17-26 kDa. This cytokine exists in a soluble form and a membrane-bound form, the active form usually being a homotrimer. TNF-alpha is produced in vivo by a variety of cell types. The primary producers of TNF-alpha are stimulated monocytes, fibroblasts, and endothelial cells. However, macrophages, T-cells, B-lymphocytes, granulocytes, smooth muscle cells, eosinophils, chondrocytes, osteoblasts, mast cells, glial cells, and keratinocytes also produce TNF-alpha after stimulation. Physiological stimuli for the synthesis of TNF-alpha include interleukin-1, bacterial endotoxins, platelet-derived growth factor (PDGF), and Oncostatin M. In fibroblasts, the synthesis of TNF-alpha is stimulated by beta-interferon, PDGF, and viral infections. In thymic stromal cells, the synthesis of TNF-alpha can be induced by nerve growth factor. TNF-alpha can also stimulate or inhibits its own synthesis, depending upon the cell type.
TNF-alpha affects many organs in the body and serves a variety of biological functions. For example, this cytokine possesses both growth stimulating properties and growth inhibiting properties. It also appears to have self regulatory properties. The varied biological impact of this cytokine makes it an attractive target for the development of compounds capable of modulating the activity of this physiologically important protein.
Thus, the need exists for new compounds that can modulate the activity of tumor necrosis factor alpha. The present invention fulfills this need and has other related advantages.